DESCRIPTION: (Applicant's Abstract) Substance abuse is a problem of significant medical, social and economic concern. Abuse of cocaine, the focus of this proposal, reached an all time high in the 1980s, and it remains responsible for a large portion of illicit drug use in the world today. Intensive research has identified a "limbic-motor" circuit in the brain that mediates reward for cocaine. Activity of this circuit can be assessed in animal models that measure two key outputs, acute cocaine locomotor activation and chronic cocaine locomotor sensitization. In the proposed studies, these behavioral endpoints are used to characterize the role of the peptide thyrotropin-releasing hormone (TRH), and other peptides derived from the TRH precursor, in rat models of cocaine addiction. These studies were suggested by preliminary data that preproTRH-derived peptides play an unexpectedly prominent role in the actions of drugs of abuse such as cocaine. Acute and chronic cocaine treatments were shown to strongly regulate preproTRH mRNA in several key brain reward regions. Further, acute cocaine caused significant regulation of TRH peptide levels in the nucleus accumbens, septal nuclei, and the hypothalamus, brain loci central to the limbic-motor circuit. Consistent with this, TRH infusions into the nucleus accumbens antagonized the acute locomotor effects of cocaine, and completely blocked its chronic locomotor sensitizing effects. Finally, in untreated animals TRH peptide levels correlated with locomotor response to a novel environment specifically in the nucleus accumbens, but not in adjacent brain loci. These findings are intriguing because locomotion to novelty may relate to drug seeking behavior. The proposed studies examine cocaine regulation of preproTRH mRNA and the TRH receptor mRNA at multiple brain sites as an efficient first screen for where preproTRH derived peptides might be acting. Effects on levels of TRH and other preproTRH-derived peptides themselves, and on TRH receptor binding, will then be measured. Additional studies will examine the downstream effects of this regulation on peripheral thyroid indices, and further characterize its pharmacology, including modulation by the hypothalamic-pituitary-adrenal axis and stress. Finally, infusion of the regulated peptides into brain sites with peptide or receptor regulation will confirm whether the peptides themselves can directly mediate acute cocaine locomotor activation and chronic cocaine locomotor sensitization. It is expected that these studies will provide a new understanding of the role of preproTRH-derived peptides in substance abuse, an understanding that may lead to new pharmacological approaches for the modification of human drug seeking behavior.